This Phase II proposal is a continuation of our successful Phase I grant whose overarching goal is to develop a more robust and accurate method for the deformable fusion of pre-operative magnetic resonance images (MRI) and intra-procedure trans-rectal ultrasound (TRUS) images to guide prostate biopsy. Prostate cancer is a major cause of death in the U.S. and biopsy is the gold-standard for its diagnosis. Each year over 1.1 million biopsies are performed in the U.S. alone at a cost of well over $1 billion. Most of these biopsies are performed under TRUS guidance in a systematic fashion but blinded to potential tumor locations because many tumors are invisible on ultrasound. This procedure is highly inef?cient and as many as 30% of serious tumors may be missed on a ?rst- time biopsy. Multi-parametric MRI (mpMRI) acquired before the biopsy can be used to de?ne potential targets and then used in conjunction with live TRUS imaging to perform targeted image-guided biopsy. A key challenge is the accurate registration (fusion) of the intra-procedure TRUS with the pre-acquired MRI. This fusion procedure is often performed using rigid registration which does not account for prostate deformation between the MRI and TRUS acquisitions. Eigen's Artemis system is one of a newer generation of devices that performs deformable mapping between MRI and TRUS. Current fusion methods (such as in Artemis), however, are highly operator dependent as they rely on semi-automated TRUS segmentation by the clinician during the procedure which is error prone, time-consuming and critically reliant on operator skill. We propose to extend the development of our strategy for deformable registration (from Phase I) based on a statistical deformation model learned from an existing, large, multi-institutional database (N=200) of MRI-TRUS prostate image pairs. We will learn the statistics of both biopsy deformation and prostate shape clusters. The model will reduce the dimensionality of the search as well as constrain the deformation. The proposed registration method will use a regional con?dence estimate for the intra-procedure interactive TRUS segmentation in order to enhance robustness by focusing the registration on the more con?dent portions of the bounding surface. We will also generate regional anisotropic estimates of registration uncertainty. These methods will streamline the clinician's work?ow by providing a more accurate and robust registration with less dependence on segmentation errors. This project is signi?cant in that it has the potential to improve the utilization of MRI-TRUS fusion guided prostate biopsy (especially outside of major academic hospitals) by alleviating the dependence of the work?ow on exact prostate segmentation from often poor quality TRUS images. In Aim 1, we will further improve our fusion algorithm, integrate it into the Artemis system and test for improved accuracy. In Aim 2, we will create an innovative research interface to our new algorithm to allow for clinical testing and then perform a two-site clinical validation in N=40 patients. We will compare our new method to the current non-rigid MRI-TRUS fusion method used in our FDA-cleared Artemis system to demonstrate improved accuracy.